The present invention relates to certain compounds which have useful antiviral activity. More particularly, the invention relates to novel antiviral compounds derived from 2,3-bis-(aryl)-3-chloropropenal derivatives, and antiviral compositions containing these compounds, and to methods of using the compositions to treat viral infections.
Infectious diseases induced by various viruses create important medical and public health problems. The viruses occurring primarily in man are spread mainly by man himself and are found in all parts of the world. The spread of such viruses are limited by inborn resistance, prior immunizing infections or vaccines, sanitary and other public health control measures, and, in a few instances, by chemoprophylactic agents.
Most effective prophylactic measures against virus infections have been the administration of a vaccine. However, in the case of human immunodeficiency virus (referred to as HIV) and herpes simplex virus (referred to as HSV), development of a vaccine is inhibited because of the specific properties of these viruses, namely, carcinogenicity and latent infection of the viruses. The carcinogenic properties of HIV is now well known and has been identified as the secondary cause of certain types of malignancies such as Kaposi's sarcoma. Moreover, the infectiousness of HIV, also referred to the AIDS virus, is difficult to diagnose since physically apparent symptoms do not appear immediately after infection and may take years to develop. If the viral infectiousness remains in the vaccine, there is the possibility of latent infection which may induce serious symptoms to the human body. There is also the possibility that an individual infected with the AIDS virus may develop clinical symptoms of other serious diseases induced by an already damaged immune system. Thus, it would be very difficult to confirm that the infectiousness of HIV was removed in a prepared vaccine and explains why there is presently no vaccine to prevent or treat AIDS. In addition, the vaccine to be used for protection to the herpes simplex infection, which has a low lethal rate, must be highly purified in order to eliminate any undesirable side effects. Accordingly, a safe vaccine for prophylaxis of infection by HSV is presently unavailable for practical use.
Considerable research and resources have recently been devoted to chemotherapeutic measures for treatment of virus infections. In general, most clinically useful antiviral drugs interfere or halt RNA or DNA synthesis. Some drugs have the property of inhibiting maturation processes in the replication cycle of viruses, while others interfere with binding or absorption of viruses to specific host cells or tissues. Still others prevent the uncoating of the viruses following absorption into the cell and some antiviral agents restrict the spread of progeny viruses from cell to cell or from infected tissues to other sites.
Difficulties with antiviral chemotherapy arise because of the obligatory dependence of viruses on host cell metabolism. Also, few virus-specific enzyme systems are as yet vulnerable to chemotherapeutic intervention. Moreover, antiviral agents that block viral replication also block normal host cell processes, and the limits between effective and toxic doses are extremely narrow. Certain of these non-selective agents are usually toxic to both infected and uninfected cells and are not used clinically because of this toxicity. Further, there are numerous complications for clinically useful antiviral agents, including a wide variety of side effects and a relatively low therapeutic index. Patients receiving these agents must be carefully monitored since some resistant virus strains have developed in patients receiving initially effective therapy.
The currently available antiviral agents include idoxuridine (IDU), an anti-herpetic drug which apparently act by being phosphorylated and incorporated into newly synthesized DNA, producing an abnormal and essentially nonfunctional DNA molecule. The drug acts on both viral and host cell DNA and is highly toxic to host cells. Clinical use of IDU has been limited to topical therapy because of its systemic toxicity. Another drug which apparently interferes with viral DNA synthesis and is effective in the treatment of herpes simplex virus infections is adenine arabinoside (Ara-A). Ara-A is useful for prophylaxis of certain infections caused by HSV type 1 and type 2. Adenine arabinoside appears less susceptible to the development of drug resistant viral strains than idoxuridine, and IUD resistant infections often respond to Ara-A treatment.
The AIDS epidemic is driving the current clinical trials that rigorously test an array of promising new drugs which have been shown to be effective in their antiviral properties in cell culture. However, among these many promising drugs that seem effective in slowing the multiplication of the AIDS virus, only azidothymidine, or AZT, has been approved for prescription use by the Food and Drug Administration (FDA). Other experimental drugs which in preliminary studies seems to suppress the production of the AIDS virus is dideoxyinosine (ddI, a less toxic AZT derivative) and interferon, but have yet not won approval by the FDA. Various other promising drugs have not been proved to be efficacious in the treatment of HIV or HSV infections in humans because of their cytotoxicity.